Pyridyl-and/or pyridoyl-(piperid-4-yl) ureas and analogues thereof

ABSTRACT

The invention concerns the preparation of compounds of formula ##STR1## and acid addition and quaternary ammonium salts thereof, wherein the dotted line represents an optional bond, Ar represents a ring system of formula ##STR2## in which Q is O, S, --CR 7  ═CR 8  --, --N═CR 8  -- and --N═N--; R 4 , R 5  and R 6  ; and R 7  and R 8  when present, each represent hydrogen or a substitutent selected from lower alkyl, lower alkenyl, lower alkoxy, NO 2 , NH 2 , haloloweralkyl, hydroxyloweralkyl, aminoloweralkyl, substituted amino, halogen, loweralkoxycarbonyl, cyano, CONH 2  and hydroxy; and additionally either R 4  and R 5  when adjacent or R 6  and R 8  when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocylic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an optionally substituted aryl or heteroaryl radical or a cycloalkyl radical containing 5 to 7 carbon atoms; R 1 , R 2 , R 3  and R 9  are each hydrogen or a lower alkyl group; n is 0 or 1; X is ═O, ═S or ═NH; Y is--O-- or a direct bond and Z is --CO--  or --CH 2  --, with the proviso that when Ar is unsubstituted phenyl and R 9  is hydrogen then y is --O--. The compounds of formula I exhibit psychotropic activity and are useful as antidepressants.

This invention relates to new piperidine derivatives, to processes forpreparing them and to pharmaceutical compositions containing them. Thisapplication is a divisional application of our co-pending applicationSer. No. 929,964, filed on Nov. 12, 1986 (now U.S. Pat. No. 4,806,552issued on Feb. 21, 1989). Said application Ser. No. 929,964 is acontinuation-in-part of our co-pending application Ser. No. 781,832,filed on Sept. 30, 1985 (now U.S. Pat. No. 4,722,930, issued on Feb. 2,1988). Said application Ser. No. 781,832 is, in turn, a divisionapplication of co-pending application Ser. No. 545,802, filed Oct. 26,1983 (now U.S. Pat. No. 4,563,466, issued on Jan. 7, 1986). Said Ser.No. 545,802, is, in turn, a continuation-in-part of co-pendingapplication Ser. No. 366,266, filed on Apr. 7, 1982 (now U.S. Pat. No.4,426,387, issued on Jan. 17, 1984). Said Ser. No. 366,266 is, in turn,a continuation of co-pending application Ser. No. 238,381, filed on Feb.25, 1981 (now abandoned).

More particularly this invention provides piperidino ureas, thioureasand guanidines which exhibit pharmaceutical activity especiallypsychotropic activity in standard pharmacological test procedures, andare potentially useful as anti-depressants. In general the compounds arespecific inhibitors of 5-hydroxytryptamine re-uptake in vitro and invivo, and therefore may also be useful in any other therapeuticapplications where such pharmacological specificity may be beneficial.

The invention provides compounds of formula: ##STR3## and acid additionand quaternary ammonium salts thereof, wherein the dotted linerepresents an optional bond, Ar represents a ring system of formula##STR4## in which Q is O, S, --CR⁷ ═CR⁸ --, --N═CR⁸ -- and --N═N--; R⁴,R⁵ and R⁶, and R⁷ and R⁸ when present, each represent hydrogen or asubstituent selected from lower alkyl, lower alkenyl, lower alkoxy, NO₂,NH₂, haloloweralkyl, hydroxyloweralkyl, aminoloweralkyl, substitutedamino, loweralkoxycarbonyl, CN, halogen, CONH₂ and hydroxy; andadditionally either R⁴ and R⁵ when adjacent or R⁶ and R⁸ when adjacent,together with the carbon atoms to which they are attached also representa fused five or six membered carbocylic or heterocyclic ring optionallycarrying one or more substituents as defined above; R is an optionallysubstituted aryl or heteroaryl radical or a cycloalkyl radicalcontaining 5 to 7 carbon atoms; R¹, R², R³ and R⁹ are each hydrogen or alower alkyl group; n is 0 or 1; X is ═O, ═S or ═NH; Y is --O-- or adirect bond and Z is --CO-- or --CH₂ --, with the proviso that when Aris unsubstituted phenyl and R⁹ is hydrogen then Y is --O--.

The term `lower` as used in connection with alkyl or alkoxy groups meansthat such groups contain 1 to 6 carbon atoms especially 1 to 4 carbonatoms. `Substituted amino` includes groups such as alkyl- ordialkyl-amino, acylamino e.g. lower alkylcarbonylamino, ureido orsulphonylamino, e.g. lower alkylsulphonylamino ordi-lower-alkylsulphonylamino.

Examples of lower alkyl groups are methyl, ethyl n-propyl, isopropyl,t-butyl, neo-pentyl and n-hexyl. Examples of lower alkoxy groups aremethoxy, ethoxy, isopropoxy, butoxy and hexoxy. Examples of cycloalkylgroups are cyclohexyl and cyclopentyl.

`Hydroxyloweralkyl` includes groups such as HO(CH₂)_(m) -- where m is 1to 4, e.g. hydroxymethyl or hydroxyethyl.

Examples of lower alkylamino and di-lower-alkylamino groups are MeNH--,EtNH--, dimethylamino, isopropylamino and butylamino.

Examples of lower alkenyl groups are vinyl, propenyl, but-1-enyl andbut-2-enyl.

Examples of haloloweralkyl groups are chloroethyl and trifluoromethyl.

`Aminoalkyl` includes groups such as NH₂ (CH₂)_(m) -- where m is 1 to 4,e.g. aminomethyl, aminoethyl.

Examples of lower alkoxycarbonyl groups are methoxy-and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine.

Examples of the group Ar when Q is O or S are ##STR5## especiallyfuran-2-yl, thiophen-2-yl, benzo[b]furan-3-yl, benzo[b]-thiophen-3-yl.Examples of Ar when Q is --CR⁷ ═CR⁸ -- are ##STR6##

When Q is --N═N-- examples are ##STR7##

When monosubstituted phenyl or pyridyl the group Ar may be for example4-t-butylphenyl, 4-cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl,4-dimethylaminophenyl, 3-vinylphenyl, 3-methylpyrid-2-yl,4-methylpyrid-2-yl, 4-methylpyrid-3-yl, 4-chloropyrid-2-yl,2-methylpyrid-4-yl or 2-bromopyrid-4-yl. When multi-substituted phenylor pyridyl the group Ar may be for example 3,4-dichlorophenyl;3,4,5-trimethylphenyl; 3,4,5-trimethoxyphenyl;3,4-dichloro-2-methylphenyl; 2,3-diethylphenyl, 3-methyl-4-vinylphenyl,2,4-dichloropyrid-6-yl, 2,4-dimethylpyrid-6-yl. Examples of Ar whenphenyl having a fused 5- or 6-membered carbocyclic or heterocyclic ringare naphth-1-yl; naphth-2-yl; benzo[1,4]dioxan-6-yl;3,4-methylene-dioxyphenyl; 1,2,3,4-tetrahydronaphth-6-yl;1,4-dihydronaphth-6-yl; benzo[b]thiophen-6-yl; indol-6-yl;benzo[b]furan-6-yl; quinol-6-yl and quinol-5-yl. Examples of Ar whenpyridyl having a fused 5 or 6 membered carbocyclic or heterocyclic ringare quinol-4-yl, quinol-2-yl, 5,6,7,8-tetrahydro-quinol-4-yl or5,6,7,8-tetrahydro-quinol-2-yl. Examples of such groups when substitutedin the fused ring are 6-methoxy-naphth-2-yl, 7-methoxy-naphth-2-yl and4-methylnaphth-2-yl. Preferred fused heterocyclic `Ar` rings haveoxygen, nitrogen or sulphur as heteratom(s).

The group R is exemplified by aryl radicals such as phenyl which can besubstituted for example by the substituents listed for R⁴, e.g. methyl(such as 4-methyl) ethyl, propyl, nitro (such as 3- or 4-nitro), hydroxy(such as 4-hydroxy), methoxy, ethoxy, fluorine, bromine, or chlorine(such as 3,4-dichloro). Heteroaryl radicals for R include thienyl (e.g.thien-2 or 3-yl), furyl (e.g. fur-2 or 3-yl) and pyridyl (e.g.pyrid-2-yl, pyrid-4-yl, pyrid-3-yl), which radicals may be substitutedas described above for the phenyl radical Ar.

Preferred values for Ar are ##STR8## in which R₄, R₅, and R₆, whenpresent, independently, are hydrogen, lower alkyl, lower alkenyl, loweralkoxy, hydroxy, hydroxyloweralkyl, fluoro, bromo, chloro,chloroloweralkyl, fluoroloweralkyl, amino, aminoloweralkyl, substitutedamino, loweralkoxycarbonyl, nitro, cyano, or amido, or

R₄ and R₅, when adjacent, together with the carbon atoms to which theyare attached also are fused five or six member carbocyclic ring with 0-2double bonds and optionally carrying one or two substituents as definedabove for said R₄ and R₅.

Other preferred values for Ar are heterocyclic systems containing one N,O or S heteroatom, or two identical N, O or S heteroatoms, in one or two5 or 6 membered rings, the ring bonded to Y being an aromatic ring otherthan a 5-membered ring containing nitrogen, said system optionallycarrying one or two substituents from

lower alkyl, lower alkenyl, lower alkoxy, hydroxy, hydroxyloweralkyl,fluoro, bromo, chloro, chloroloweralkyl, fluoroloweralkyl, amino,aminoloweralkyl, substituted amino, loweralkoxycarbonyl, nitro, cyano,or amido.

Preferred values for R are phenyl or phenyl substituted by one or two ofthe same substituents selected from

lower alkenyl, lower alkoxy, lower alkyl, hydroxy, hydroxyloweralkyl,fluoro, bromo, chloro, chloroloweralkyl, fluoroloweralkyl, amino,aminoloweralkyl, substituted amino, loweralkoxycarbonyl, nitro, cyano oramido.

Other preferred values for R are thienyl, furyl or pyridyl substitutedby one or two of the same substituents selected from

loweralkyl, lower alkenyl, lower alkoxy, hydroxy, hydroxyloweralkyl,fluoro, bromo, chloro, chloroloweralkyl, fluoroloweralkyl, amino,aminoloweralkyl, substituted amino, loweralkoxycarbonyl, nitro cyano oramido.

Most preferably Ar is phenyl substituted by one or more alkyl or alkoxygroups of 2 or more carbon atoms, e.g. 4-ethylphenyl, 3,4dimethylphenyl, 3,4-dimethoxyphenyl; phenyl having a fused 5 or 6membered carbocyclic ring, e.g. naphth-1-yl, naphth-2-yl, such groupsbeing optionally substituted by lower alkyl, lower alkoxy, halogen,nitro, trifluoromethyl, amino, lower alkylamino (e.g. methylamino)diloweralkylamino (e.g. dimethylamino) and cyano.

Preferably n is O, R⁹ is hydrogen or methyl and R¹ is hydrogen.Preferably X is oxygen.

Preferably Z is --CO-- and R is phenyl or phenyl substituted in the4-position by lower alkoxy, e.g. methoxy.

Y is preferably a direct bond.

When Z is --CH₂ --, R is preferably phenyl.

Preferred compounds of the invention are1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea;1-benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea;1-benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea;1-benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)piperid-4-yl]urea;1-benzoyl-3-[-(3,4-dimethylbenzyl)piperid-4-yl]urea;1-benzoyl-3-[1-(indan-5-ylmethyl)piperid-4-yl]urea;1-benzoyl-3-[1-(1-(naphth-2-yl)ethyl)piperid-4-yl]urea;N-[[[1-[(6-Fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-3-pyridinecarboxamide;andN-[[[1-[(6-Fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-4-pyridinecarboxamide.

Examples of acid addition salts are those formed from inorganic andorganic acids and in particular pharmaceutically acceptable acidaddition salts from such as the hydrochloride, hydrobromide,hydroiodide, sulphate, nitrate, phosphate, sulphonate (such as themethanesulphonate and p-toluenesulphonate), acetate, maleate, citrate,fumarate, tartrate, malonate and formate.

Compounds of formula I were tested for psychotropic activity by theirability to inhibit p-chloroamphetamine (pCA) induced hyperactivityand/or by their ability to inhibit 5-hydroxytryptamine (5-HT) uptake inbrain slices.

The following test procedure was used to test for ability to inhibitp-chloroamphetamine induced hyperactivity.

Three groups of 4 female mice (20-24 g) receive the test compounds (50mg/kg po) and a fourth group the requisite volume of vehicle. Thirtyminutes later all the animals are given 20 mg/kg p-chloroamphetamine(pCA) ip. The grouped mice are placed immediately in square plasticcages in activity monitors and their motor activity recorded over theperiod 10-30 minutes post pCA. This procedure is repeated three moretimes so that four groups of mice are used per treatment and eachactivity monitor is used with all treatments in turn. The inhibition ofpCA induced hyperactivity is calculated thus: ##EQU1## where C=meanactivity of control groups 10-30 minutes post pCA.

T=mean activity of treated groups 10-30 minutes post pCA.

This test is used as an in vivo screen for detection of5-hydroxytryptamine uptake inhibitors.

Compounds giving >50% inhibition are considered of special interest. Insuch a test the following compounds were particularly active:

    ______________________________________                                                              % Inhibition of                                                               pCA induced                                             Compound              hyperactivity                                           ______________________________________                                        1-Benzoyl-3-[1-(naphth-2-ylmethyl)-                                                                 67.5%                                                   piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(naphth-1-ylmethyl)-                                                                 56.4%                                                   piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(4-isopropylbenzyl)-                                                                 49%                                                     piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(5,6,7,8-tetrahydro-                                                                 69.4%, 73.5%                                            naphth-2-ylmethyl)piperid-4-yl]urea                                           1-Benzoyl-3-[1-(3,4-dimethylbenzyl)-                                                                68.9%                                                   piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(indan-5-ylmethyl)-                                                                  59.3%                                                   piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(1-naphth-2-yl)ethyl]-                                                               71.7%                                                   piperid-4-yl]urea                                                             1-Benzoyl-3-[1-(4-ethylbenzyl)-                                                                     72.9%                                                   piperid-4-yl]urea                                                             ______________________________________                                    

Compounds of formula I were tested for ability to inhibit5-hydroxytryptamine (5-HT) uptake in brain slices using the followingprocedure:

The effects of test compound on the neuronal uptake of5-hydroxytryptamine into slices of cerebral cortex prepared from ratbrain is determined according to the method described by Snyder, Greenand Hendley, Kinetics of H³ -norepinephrine accumulation into slicesfrom different regions of the rat brain (J. Pharm. exp. Therap. 164:90-102) (1968). Concentration-response curves for the test compound andfor the standard agent, imipramine, are obtained. The potency of thetest compound is expressed in proportion to that of imipramine. Thus,the potency ratio for the test compound - ##EQU2## Compounds notachieving 50% inhibition are considered inactive.

In such a test the compound1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea above wasparticularly active having a potency ratio of 8.8 (imipramine=1.0).

In vivo 5-HT uptake inhibition was also demonstrated for compounds ofthe invention by a procedure involving 5-hydroxy-L-tryptophan (5-HTP)induced behavioural syndrome. Mice given a high dose of 5-HTP exhibit abehavioural syndrome consisting of tremor, hind limb abduction, lateralhead weaving and forepaw treading. In addition to these signs rats alsoexhibit head twitching and circling behaviour. In the followingexperiments the syndrome was said to be present if mice exhibited atleast 3 and rats at least 4 of these signs. When animals are given a lowdose of 5-HTP, which does not itself produce the syndrome, it can beproduced by pretreatment with 5-HT uptake inhibitors. Thus, this testcan be used as an indication of in vivo 5-HT uptake inhibition.

(a) Dose/response study in mice

Groups of 12 (2 subgroups of 6) female mice (18-22 g) were used perdose, each group being housed in a separate cage for the duration of theexperiment. Mice were dosed p.o. with either test compound or vehicle(0.5% HPMC) and 30 minutes later received a threshold dose of 5-HTP (80mg/kg i.p.) and were placed in perspex cylinders (12" diameter). After afurther 20 minutes the mice were observed for 5 minutes for the presenceor absence of the syndrome.

The dose that produced the syndrome in 50% of the mice was calculatedusing the method of Litchfield and Wilcoxon, J. Pharm. Exp. Ther. 96,99-113 (1949).

(b) Dose/Response study in rats

Groups of 6 male rats (150 g) were dosed with test compound suspended inHPMC. Thirty minutes later 5-HTP (70 mg/kg i.p.) was given and thenumber of signs/rat recorded between 20 and 35 minutes post 5-HTP.Linear regression analysis of the results was performed and the ED₅₀calculated from this.

The results found for1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (A) and for theantidepressant clomipramine are shown below:

    ______________________________________                                                   ED.sub.50 values for potentiation                                             of 5-HTP syndrome in:                                              Compound     Mice (mg/kg po)                                                                            Rats (mg/kg ip)                                     ______________________________________                                        A            7.2          5.3                                                 clomipramine 18           39.2                                                ______________________________________                                    

In a preferred embodiment this invention provides a compound of formulaIA ##STR9## or salts thereof, wherein R¹² is 3- or 4-pyridyl, R¹¹ ishydrogen or fluorine, and is bonded to any of the vacant naphthalenering positions, e.g. 5- or 7-. In formula IA, R¹¹ is preferably hydrogenin which case the compound isN-[[[1-[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-3-pyridinecarboxamide(C) orN-[[[1-[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-4-pyridinecarboxamide (D).

Representative compounds of formula IA were tested for their ability toinhibit pCA induced syndrome in rats by the standard procedure describedbelow:

Inhibition of p-chloroamphetamine (pCA)-induced stereotypy

Vehicle or drug (5 dose levels) were administered p.o. to six groups of6-8 male Sprague-Dawley rats (300-400 g) followed, 90 minutes later, bypCA (10 mg/kg i.p.). The animals were then placed in individualobservation chambers and, 30 minutes after pCA administration, theintensity of the pCA-induced 5-HT syndrome was assessed according to thefollowing scoring system:

    ______________________________________                                        hind-limb abduction                                                           head-weaving        0, 1, 2 or 3 according to severity                        fore-paw treading                                                             tremor              0 (absent) or 1 (present)                                 ______________________________________                                    

Therefore, the maximum score for each animal was 10.

The inhibition of pCA induced stereotypy is calculated for each doselevel as follows: ##EQU3## where C=control group total score at 30minutes post pCA.

T=group total score of treated group at 30 minutes post pCA.

For each dose a % effect is calculated.

The results obtained from the tests using 5 different dose levels of thedrug allow the ED₅₀ value (i.e. the dose required to produce 50%inhibition of pCA induced stereotypy) to be calculated.

In the aforementioned test the representative compounds C and Dantagonised pCA-induced stereotypy in a dose-dependent manner and gavethe following ED₅₀ values:

    ______________________________________                                        Compounds of Formula I                                                                          ED.sub.50 (mg/kg)                                           ______________________________________                                        C                 2.5                                                         D                 3.8                                                         ______________________________________                                    

The test was carried out using the free bases for compound C. Compound Bwas tested in the form of the succinate salt and the results correctedfor amount of active material.

At 50 mg/kg the compound C showed a 99% inhibition of syndrome.

The compound (C) was also tested for its ability to potentiate5-hydroxy-L-tryptophan induced behavioural syndrome in rats. The testprocedure is described below

Potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour

Groups of 10 male Sprague-Dawley rats (310-360 g) were dosed p.o. withvehicle or drugs. Ninety minutes later 5-HTP (50 mg/kg s.c.) wasadministered and the animals placed in individual observation chambers(peripheral decarboxylation was prevented by 25 mg/kg i.p. carbidopaadministered 60 minutes before 5-HTP). Head shakes were counted over theperiod 30-45 minutes after 5-HTP and the intensity of the 5-HT syndromewas scored immediately afterwards using the system described for the pCAprocedure above. Percentage potentiation of syndrome was calculated asfollows:

    ______________________________________                                        hind-limb abduction                                                                           0, 1, 2 or 3 according to severity                            head-weaving                                                                  tremor          0 (absent) or 1 (present)                                     fore-paw treading                                                             Percentage potentiation was calculated from the following:                     ##STR10##                                                                    ______________________________________                                    

In this test the compound (C) as the citrate salt had an ED₅₀ value of5.0 mg/kg (corrected for amount of base).

In vitro tests have shown that compounds of formula IA also have amarked degree of selectivity in inhibiting uptake of 5-HT into rat brainsynaptosomes relative to uptake of ³ H noradrenaline. The test procedureinvolved obtaining synaptosomal preparations from male Sprague Dawleyrats according to the method of Grey and Whittaker* as modified by Woodand Wyllie**. Aliquots of the synaptosomal preparation were thenincubated with tritrated noradrenaline (NA) or 5-HT at a temperature of37° C. for 4 minutes. The active synaptosomal accumulation of labelledsubstrate was measured by filtration and scintillation counting. Theeffect at a range of concentrations of test compound enabled IC₅₀ valuesand selectivity ratios to be calculated. The values found for compound Aare shown below:

    ______________________________________                                                IC.sub.50 (μM)                                                                                     Selectivity                                   Compound  5-HT uptake    NA     Ratio                                         ______________________________________                                        A         0.044          20.0   455                                           ______________________________________                                    

This invention also provides processes for preparing compounds offormula I or acid addition or quaternary ammonium salts thereof. Ingeneral the compounds of formula I are prepared by building up themolecule from the appropriate starting materials by known reactions.Accordingly a first process for preparing a compound of formula Icomprises reacting a compound of formula II ##STR11## wherein the dottedline, R, R¹, R³, Z and X are as defined in connection with formula I,with a compound of formula III

    Ar--Y--CHR.sup.9 --(CHR.sup.2).sub.n --W                   (III)

wherein Ar, Y, n, R² and R⁹ are as defined above and W represents aleaving group, such as halogen, (e.g. chlorine, bromine or iodine), anorganic sulphonyloxy radical (e.g. tosyloxy, mesyloxy), or a radical offormula --OSO₂ OR where R is W--A--, i.e. a sulphate.

The reaction is preferably carried out in the presence of base, e.g.potassium carbonate, triethylamine; otherwise the reaction may becarried out by heating in the presence of an inert solvent, e.g.toluene.

A second general process for preparing compounds of formula I wherein Xis O or S and R³ is hydrogen comprises reacting a compound of formula##STR12## wherein Ar, Y, R¹, R², R⁹ and n are as hereinbefore definedwith a compound of formula

    R--Z--N═C═X                                        (V)

wherein R and Z are as hereinbefore defined and X is O or S. Such areaction can be effected at room temperature. The starting materials offormula (IV) wherein R¹ is hydrogen may be prepared by methods describedin our U.K. Patent Specification No. 1,345,872. The starting materialsof formula IV wherein R¹ is lower alkyl may be prepared by alkylatingcorresponding compounds of formula IV wherein R¹ is hydrogen, or bymethods analogous to those described in Specification No. 1,345,872.

A further process for preparing compounds of formula I comprisesreacting a compound of formula IV as defined hereinbefore with acompound of formula ##STR13## wherein R, R³ and Z are as defined aboveand X is as defined above and if desired converting the product to anacid addition salt.

This process may be performed in the absence of solvent but is usuallycarried out by heating the reactants in the presence of a suitable inertorganic solvent, for example toluene, pyridine, xylene, chlorobenzene,dimethylformamide or dioxan. Pyridine is the preferred solvent. Often itis convenient to reflux the reactants in the solvent until the reactionis complete. High yields e.g. 80-90% can be obtained. Preferably thesolvent has a boiling point greater than 100° C.

It is preferred to use equimolar amounts of the reactants.

A still further process for preparing compounds of formula I ashereinbefore defined wherein Z is --CO-- comprises acylating a compoundof formula ##STR14## wherein the dotted line, Ar, X, Y, R², R³, R⁹, nand R¹ are as hereinbefore defined with an acylating agent containingthe group --COR. Examples of acylating agents are reactive derivativesof acids of formula RCOOH such as the acid halides (e.g. chloride,bromide) and the anhydride and activated esters as used in peptidechemistry. Other methods of acylation are well known in the art such asthose employing coupling agents such as carbodiimides, e.g.dicyclohexylcarbodiimide.

Compounds of formula VI may be prepared by hydrolysis of compounds offormula I wherein Z is --CO--.

Compounds of formula I may also be prepared by reducing a compound offormula VII or VIII ##STR15## in which formulae Z, X, Ar, Y, n, R, R¹,R², R³ and R⁹ are as hereinbefore defined and B.sup.⊖ represents ananion, e.g. a halide ion. For example catalytic hydrogenation when X═O,e.g. in the presence of Raney nickel or platinum catalyst givespiperidine compounds of formula I. The reduction may also be effected bya process described and claimed in our U.K. Patent Specification No.1542137. Such a reduction process employs an alkali metal borohydride ina secondary alkanol having 3-5 carbon atoms, e.g. isopropanol.Alternatively reduction of compounds of formula VIII using an alkalimetal borohydride in methanol gives dehydropiperidine compounds offormula I.

Yet a further process for preparing a compound of formula I comprisesreacting a compound of formula

    Ar--Y--CHR.sup.9 --(CHR.sup.2).sub.n --OH                  (IX)

wherein Ar, Y, n, R² and R⁹ are as hereinbefore defined with a compoundof formula II, when X═O, in the presence of a catalyst, e.g. a nickelcatalyst such as Raney nickel.

Compounds of formula I wherein X is ═O or ═NH may also be prepared bytreating a corresponding compound of formula (X) ##STR16## wherein thedotted line Ar, Y, R, R¹, R², R³, R⁹ and B.sup.⊖ are as hereinbeforedefined, n is 1 and R¹⁰ is an organic quaternizing group which can beremoved under mild conditions, e.g. by hydrogenolysis, that do notaffect the rest of the molecule. For example, when R¹⁰ is an arylmethylradical, such as benzyl, hydrogenolysis under standard conditions, e.g.using an appropriate catalyst such as a palladium on carbon, platinum ornickel catalyst, gives compounds of formula I. Methods for effectingthis reaction are given in our U.K. Patent Specification No. 1,399,608.Suitably solvents include alkanols such as methanol.

Starting materials of formula X may be prepared by reacting a compoundof formula III as defined above with a compound of formula ##STR17##wherein R¹⁰, R³, R¹ and R are as herein defined and X is ═O or ═NH.

Compounds of formula I wherein Y is --O-- may also be prepared byreacting a compound of formula ##STR18## wherein hal represents halogenand the dotted line R, R¹, R², R³, R⁹, n, X and Z are as hereinbeforedefined with a compound of formula

    ArOH                                                       (XIII)

wherein Ar is as hereinbefore defined. This reaction is convenientlycarried out by heating reactants in an inert solvent such asdimethylsulphoxide, in the presence of base, e.g. sodium hydride.Preferably hal represents bromine or chlorine.

Yet a further process for preparing compounds of formula I wherein X isNH and the dotted line is absent, comprises reacting a compound offormula ##STR19## wherein R, and R³ are as hereinbefore defined with acompound of formula IV as hereinbefore defined. This reaction may becarried out in an inert solvent e.g. toluene with heating.

Once a compound of formula I having a reactive substituent group hasbeen prepared then that compound may be converted in known manner toother compounds of formula I. For example when Ar is a group having alower alkoxy or aryl lower alkoxy substituent on an aromatic ringdealkylation produces a corresponding compound of formula I wherein Arcarries a hydroxy substituent. When Ar is a group having nitro on anaromatic ring then reduction (e.g. catalytic hydrogenation) can convertthe nitro group to an amino group. Such amino groups may be acylated.

The aforementioned processes may also include the step of conversion ofan acid addition salt into the free base form or vice versa.Quaternisation of the tertiary nitrogen of the piperidine ring may beincluded as an optional after step, e.g. using alkyl or aryl lower alkylhalides, e.g. methyl iodide, benzyl chloride.

Starting materials used in the above mentioned processes are knowncompounds or may be prepared by analogous processes. For example, acompound of formula II wherein X═O may be prepared by reducing thecorresponding compound of formula (XIV) ##STR20## using for examplecatalytic hydrogenation. Compounds of formula XIV wherein R³ is H and Xis O or S may be prepared by reacting a 4-aminopyridine with a compoundof formula RZNCX. Compounds of formula I or XIV wherein Z is --CO-- andR³ is lower alkyl may be prepared by alkylating a corresponding compoundof formula I or XIV wherein R³ is hydrogen (e.g. using an alkali metalhydride and an alkyl halide).

Compounds of formula VIII may be prepared by reacting a compound offormula III wherein W is halogen, especially bromine, with a compound offormula XIV.

Two general reactions for preparing starting materials of formula II areillustrated in the scheme below: ##STR21##

If necessary, in any of the reactions herein described, reactivesubstituent groups may be blocked during a reaction and released at alater stage. For example an amino substituent may be protected by abenzyloxy-carbonyl group which is removable using H₂ /Pd at the end of areaction. Dehydropiperidine compounds of formula I (in which theoptional bond is present) are also useful as intermediates for preparingthe piperidines of formula I, being converted by reduction. Acylureacompounds of formula I are also useful as intermediates for preparingother acylurea compounds of formula I, by hydrolysing to give the ureaof formula VI and re-acylating.

This invention also includes pharmaceutical compositions containing asactive ingredient an active compound of formula I as above defined. Theactive compound may be finely comminuted if desired. In addition to theactive ingredient, the compositions also contain a pharmaceuticallyacceptable carrier. Any suitable carrier known in the art can be used toprepare the pharmaceutical compositions. In such a composition, thecarrier may be a solid, liquid or mixture of a solid and a liquid. Solidform compositions include powders, tablets and capsules. A solid carriercan be one or more substances which may also act as flavouring agents,lubricants, solubilisers, suspending agents, binders, ortablet-disintegrating agents; it can also be an encapsulating material.In powders the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 to 99,preferably 10-80% of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, andcocoa butter. The term "composition" is intended to include theformulation of an active ingredient with encapsulating material ascarrier to give a capsule in which the active ingredient (with orwithout other carriers) is surrounded by carrier, which is thus inassociation with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable sterile liquid carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufficiently soluble it can be dissolvedin normal saline as a carrier; if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene glycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable. In other instances composition can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilised by intramuscular,intraperitoneal or subcutaneous injection. In many instances, a compoundis orally active and can be administered orally either in liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form. Insuch form, the composition is sub-divided in unit doses containingappropriate quantities of the active ingredients; the unit dosage formcan be a packaged composition, the package containing specificquantities of composition, for example packeted powders or vials orampoules. The unit dosage form can be a capsule, cachet or tabletitself, or it can be the appropriate number of any of these in packageform. The quantity of active ingredient in a unit dose of compositionmay be varied or adjusted from 5 mg or less to 500 or more, according tothe particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence of carrier wherethe compounds are in unit dosage form.

A further aspect of this invention includes a method of alleviatingdepression in a warm blooded animal afflicted with depression, whichmethod comprises administering to said animal an effective amount of acompound of formula I as defined above.

The amount of compound used will depend on the compound employed, theseverity and nature of the depression and the animal being treated. Withlarge animals (about 70 kg body weight) by the oral route the dose ispreferably from about 5 to about 75 mg and most preferably from about 10to about 25 mg every four hours or as needed. By the parenteral routethe dosage is preferably from about 2 to about 35 mg as needed. Ideallytherapy should be initiated with lower dosages, the dosage thereafterbeing increased until the desired anti-depressive effect is obtained.

A further aspect of this invention provides chemical intermediates forthe compounds of formula I which intermediates have the formula VI ashereinbefore defined wherein R³ is hydrogen, and formula VIII ashereinbefore defined.

The following examples illustrate the invention:

EXAMPLE 1 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

4-Benzoylureidopiperidine (1.28 g, 0.005 m), 2-(bromomethyl)naphthalene(1.1 g, 0.005 m) and triethylamine (0.6 g, 0.006 m) in dimethylformamide(25 cm³) were stirred at room temperature for 23 hours. Water was addedand the precipitated solid filtered off and washed well with water. Thesolid was suspended in warm ethanol, acidified with ethanolic HCl andthen heated until all the solid had dissolved. The title compoundcrystallised and was collected as the hydrochloride salt, hemihydrate(1.6 g), m.p. 232°-234° C.

Analysis: C₂₄ H₂₅ N₃ O₂.HCl.1/2H₂ O requires: C, 66.58; H, 6.29; N,9.70%. Found: C, 66.57; H, 6.43; N, 9.45%.

EXAMPLE 2 1-Benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea

1-Chloromethylnaphthalene (0.88 g, 0.005 m), 4-benzoylureidopiperidine(1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25cm³) were stirred at room temperature for 24 hours. Water was added andthe precipitated solid filtered off. The solid was suspended inisopropylalcohol and acidified with ethanolic HCl. The title compoundwas filtered off and dried as the hydrochloride salt, hemihydrate (1.2g), m.p. 185°-186° C.

Analysis: C₂₄ H₂₅ N₃ O₂.HCl.1/2H₂ O requires: C, 66.58; H, 6.29; N,9.70%. Found: C, 66.19; H, 6.52; N, 9.72%.

EXAMPLE 3 1-Benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea

4-Isopropylbenzyl chloride (0.84 g, 0.005 m), 4-benzoylureidopiperidine(1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25cm³) were stirred at room temperature for 24 hours. Water was added andthe precipitated solid filtered off. The solid was suspended inisopropylalcohol and acidified with ethanolic HCl. The title compoundwas filtered off and dried (1.2 g), m.p. 240°-242° C. as thehydrochloride salt, hemihydrate.

Analysis: C₂₃ H₂₉ N₃ O₂.HCl1/2H₂ O requires: C, 65.01; H, 7.35; N,9.89%. Found: C, 65.24; H, 7.66; N, 9.67%.

EXAMPLE 4 1-Benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)piperid-4-yl]urea

6-Methoxynaphth-2-ylmethanol (0.94 g, 0.005 m) in dry benzene (10 cm³)was refluxed with thionyl chloride (3 cm³) for 3 hours. The solvent wasevaporated and the residue treated with benzene (3×) and evaporated.4-Benzoylureidopiperidine (1.28 g, 0.005 m), triethylamine (1.5 g, 0.015m) and dimethylformamide (25 cm³) was added to the residue and thereaction mixture stirred at 50° C. for 2 hours. The solution wasfiltered and then diluted with water. The precipitated solid was washedwith water, dissolved in chloroform and the chloroform extract washedwith water and dried (MgSO₄). Evaporation gave a solid which wassuspended in ethanol, acidified with ethanolic HCl and heated until allthe solid had dissolved. On cooling the title compound crystallised andwas filtered and dried as the hydrochloride, hemihydrate (1.3 g), m.p.243°-244° C.

Analysis: C₂₅ H₂₇ N₃ O₃.HCl.1/2H₂ O requires: C, 64.85; H, 6.31; N,9.07%. Found: C, 64.59; H, 6.40; N, 8.90%.

EXAMPLE 5 3-Benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea

1,4-Benzodioxan-6-ylmethanol (1.55 g, 9.34 mmol) and thionyl chloride(1.7 g, 14.29 mmol) were refluxed in sodium-dried diethyl ether (30 cm³)for 3 hours then the solvent and excess thionyl chloride evaporated. Theresidue was dissolved in toluene (20 cm³), thionyl chloride (1.7 g,14.29 mmol) was added and the solution heated and stirred at 80° C. for3 hours. Evaporation of the solvent gave a residue.4-Benzoylureidopiperidine (2.0 g, 8.1 mmol) and triethylamine (1.09 g,10 mmol) were added to the residue and refluxed in isopropyl alcoholovernight. The isopropyl alcohol was evaporated and the residuetriturated with water. The water was decanted and the residuecrystallised from isopropyl alcohol (1.64 g).

The base was suspended in refluxing isopropyl alcohol, ethanolic HCl wasadded and the mixture filtered. The filtrate was cooled at 5° C.overnight and the title compound collected and dried as thehydrochloride, quarterhydrate (1.46 g), m.p. 231°-235° C.

Analysis: C₂₂ H₂₅ N₃ O₄.HCl.1/4H₂ O requires: C, 60.55; H, 6.12; N,9.63%. Found: C, 60.74; H, 6.27; N, 9.38%.

EXAMPLE 6 1-Benzoyl-3-[1-(3,4-dimethylbenzyl)piperid-4-yl]urea

3,4-Dimethylbenzyl alcohol (0.68 g, 0.005 m) in dry benzene (10 cm³) wastreated with thionyl chloride (3 cm³) and refluxed for 3 hours. Thesolvent was evaporated and the residue treated with benzene (3 times)and evaporated. 4-Benzoylureidopiperidine (1.28 g, 0.05 m),triethylamine (1.5 g, 0.015 m) and dimethylformamide (25 cm³) were addedto the residue and the reaction mixture stirred at 50° C. for 2 hours.The solution was filtered and the filtrate diluted with water. Theprecipitated solid was filtered, dissolved in chloroform and washed wellwith water, dried (MgSO₄) and evaporated to give a solid. The solid wassuspended in ethanol and acidified with ethanolic HCl to give the titlecompound, which was recrystallised from ethanol as the hydrochloride,quarterhydrate, m.p. 239°-240° C.

Analysis: C₂₂ H₂₇ N₃ O₂.HCl.1/4H₂ O requires: C, 65.01; H, 7.07; N,10.34%. Found: C, 64.62; H, 7.05; N, 10.15%.

EXAMPLE 7 1-Benzoyl-3-[1-(3-aminobenzyl)piperid-4-yl]urea

1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13)was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and roomtemperature until no more hydrogen was taken up. The catalyst wasfiltered and the filtrate evaporated. The residue was dissolved in waterand basified with 0.880 ammonia. The precipitated solid was filtered,washed well with water, dried, treated with charcoal, and evaporated togive the title compound, (1.9 gms). This was recrystallised fromethanolic HCl to give the dihydrochloride salt, monohydrate, m.p.194°-195° C.

EXAMPLE 81-Benzoyl-3-[1-(3-dimethanesulphonylaminobenzyl)piperid-4-yl]urea

Methanesulphonyl chloride (0.55 g) was added at room temperature to astirred solution of the product of Example 7 (1.69 g) and triethylamine(0.5 g) in chloroform (10 cm³). After addition was complete the solutionwas allowed to stir for 3 hours, then washed with water, dried, andevaporated. The residue was purified by trituration with ethanol atreflux. The product was suspended in ethanol, acidified with ethanolicHCl, heated for 5 minutes, cooled, and the title hydrochloride collectedby filtration (0.5 g), m.p. 189°-91° C.

Analysis: C₂₂ H₂₈ N₄ O₆ S₂.HCl.1/2H₂ O requires: C, 47.69; H, 5.46; N,10.11%. Found: C, 47.56; H, 5.25; N, 9.74%.

EXAMPLES 9 TO 35

Using the procedure of Example 1 the following compound of formula I areobtained by reacting the appropriate compound of formula III wherein Wis chlorine or bromine with 4-benzoylureidopiperidine:

    ______________________________________                                        Example No.                                                                              Compound                                                           ______________________________________                                         9.        1-Benzoyl-3-[-(2-[naphth-1-yloxy]ethyl)-                                      piperid-4-yl]urea (m.p. of HCl, quarter-                                      hydrate salt = 226-229° C.).                                10.        1-Benzoyl-3-[1-(3,4-dichlorobenzyl)-                                          piperid-4-yl]urea (m.p. of HCl,                                               hemihydrate salt = 244-245° C.).                            11.        1-Benzoyl-3-[1-(4-t-butylbenzyl)piperid-                                      4-yl]urea, (m.p. of HCl, quarter-                                             hydrate salt = 202-204° C.).                                12.        1-Benzoyl-3-[1-(4-n-butoxybenzyl)-                                            piperid-4-yl]urea, (m.p. of HCl,                                              hemihydrate salt = 214-217° C.).                            13.        1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-                                        4-yl]urea, (m.p. of HCl, quarterhydrate                                       salt = 255-257° C.).                                        14.        1-Benzoyl-3-[1-(5,6,7,8-tetrahydro-                                           naphth-2-ylmethyl)piperid-4-yl]urea                                           (m.p. of HCl salt = 233-5° C.).                             15.        1-Benzoyl-3-[1-(4-ethylbenzyl)piperid-                                        4-yl]urea, (m.p. of HCl salt = 234-236° C.).                16.        1-Benzoyl-3-[1-(3,4-dibromobenzyl)-                                           piperid-4-yl]urea, (m.p. of HCl                                               salt = 228-230° C.).                                        17.        1-Benzoyl-3-[1-(2,5-dimethylbenzyl)-                                          piperid-4-yl]urea, (m.p. of HCl                                               salt = 231-232° C.).                                        18.        1-Benzoyl-3-[1-(4-n-propoxybenzyl)-                                           piperid-4-yl]urea, (m.p. of HCl                                               salt = 232-234° C.).                                        19.        1-Benzoyl-[1-[2-(naphth-2-oxy)ethyl]-                                         piperid-4-yl]urea (m.p. of HCl                                                salt = 215-218° C.).                                        20.        1-Benzoyl-3-[1-(indan-5-ylmethyl)-                                            piperid-4-yl]urea, (m.p. of HCl                                               salt = 253-6° C.).                                          21.        1-Benzoyl-3-[1-(1-(naphth-2-yl)ethyl)-                                        piperid-4-yl]urea, (m.p. of HCl                                               salt = 172-4° C.).                                          22.        1-Benzoyl-3-[1-(4-methyl-3-nitrobenzyl)-                                      piperid-4-yl]urea, (m.p. of HCl                                               salt = 232-234° C.).                                        23.        1-Benzoyl-3-[1-(3-bromo-4-methylbenzyl)-                                      piperid-4-yl]urea.                                                 24.        1-Benzoyl-3-[1-(quinol-4-ylmethyl)-                                           piperid-4-yl]urea, (m.p. of sesquihydro-                                      chloride salt = 211-213° C.).                               25.        1-Benzoyl-3-[1-(quinol-2-ylmethyl)-                                           piperid-4-yl]urea, (m.p. of di-HCl                                            salt = 213-215° C.).                                        26.        1-Benzoyl-3-[1-(3,5-dimethylbenzyl)-                                          piperid-4-yl]urea, (m.p. of HCl,                                              quarterhydrate salt = 248-252° C.).                         27.        1-Benzoyl-3-[1-(2,4-dimethylbenzyl)-                                          piperid-4-yl]urea, (m.p. of HCl,                                              quarterhydrate salt = 230-232° C.).                         28.        1-Benzoyl-3-[1-(3-bromobenzyl)piperid-                                        4-yl]urea (m.p. of HCl, quarterhydrate                                        salt = 222-224° C.).                                        29.        1-Benzoyl-3-[1-(3-iodobenzyl)piperid-                                         4-yl]urea (m.p. of HCl salt = 217-219° C.).                 30.        1-Benzoyl-3-[1-(pyrid-4-ylmethyl)-                                            piperid-4-yl]urea (m.p. of di-HCl                                             salt = 236-238° C.).                                        31.        1-Benzoyl-3-[1-(3-trifluoromethylbenzyl)-                                     piperid-4-yl]urea (m.p. of HCl salt =                                         241-243° C.).                                               32.        1-Benzoyl-3-[1-(4-methoxycarbonyl-                                            benzyl)piperid-4-yl]urea (m.p. of HCl                                         salt = 247-249° C.).                                        33.        1-Benzoyl-3-[1-(6-methylnaphth-2-yl-                                          methyl)piperid-3-yl]urea (m.p. of HCl,                                        hemihydrate salt = 250-253° C.).                            34.        1-Benzoyl-3-[1-(1-[benzofuran-2-yl]-                                          ethyl)piperid-4-yl]urea (m.p. of HCl                                          salt = 148-149° C.).                                        35.        1-[1-(5-Acetamido-2-hydroxybenzyl)-                                           piperid-4-yl]-3-benzoylurea                                                   (m.p. of HCl, 3/4 hydrate salt =                                              230-232° C.).                                               ______________________________________                                    

EXAMPLE 36 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]thiourea

4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042 m) andbenzoylisothiocyanate (0.69 g, 0.0042 m) in toluene (120 cm³) wasstirred at room temperature for 6 hours. The solvent was evaporated andthe gum dissolved in isopropyl alcohol and acidified with ethanolic HCl.The solvent was evaporated and the residue dissolved in ethyl acetate.The title compound crystallised and was filtered and dried as themonohydrochloride quarterhydrate salt, m.p. 212°-214° C.

EXAMPLE 37 1-[1-(Naphth-2-ylmethyl)piperid-4-yl]-3-(then-2-oyl)urea

4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0047 m) and1-(then-2-oyl)urea (0.65 g, 0.0042 m) in pyridine (5 cm³) was refluxedfor 9.5 hours. The solvent was evaporated, water added, and theprecipitated title compound filtered and washed well with water. Thiswas recrystallised from ethanol, converted to the hydrochloride salt inethanol with ethanolic HCl, and recrystallised from ethanol, 0.5 g, atthe hydrochloride, m.p. 217°-219° C.

EXAMPLE 38 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]quanidine

4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042 m) and benzoylcyanamide (0.67 g, 0.0042 m) in toluene (100 cm³) were refluxed for 15hours. The solvent was evaporated and the residue recrystallised fromthe minimum amount of isopropyl alcohol and recrystallised twice morefrom ethanol to give 0.65 g of the title compound, m.p. dihydrochloridequarter hydrate, m.p. 260°-262° C.

EXAMPLES 39-42

Using a procedure analogous to Example 374-amino-1-(naphth-2-ylmethyl)piperidine is reacted with each of thefollowing ureas:

3,4-dimethylbenzoylurea,

3-trifluoromethylbenzoylurea,

4-nitrobenzoylurea

and 1-(pyrid-4-oyl)urea to give the following compounds:

    ______________________________________                                        Example No.                                                                             Compound                                                            ______________________________________                                        39.       1-(3,4-Dimethylbenzoyl)-3-[1-(naphth-                                         2-ylmethyl)piperid-4-yl]urea                                                  (m.p. of HCl, quarterhydrate = 223-226° C.).                 40.       1-(1-(Naphth-2-ylmethyl)piperid-4-yl]-3-                                      (3-trifluoromethylbenzoyl)urea                                                (m.p. 251-253° C.).                                          41.       1-[1-(Naphth-2-ylmethyl)piperid-4-yl]-                                        3-(4-nitrobenzoyl)urea (m.p. of HCl salt =                                    264-5° C.).                                                  42.       (1-(Pyrid-4-oyl)-3-[1-(naphth-2-ylmethyl)-                                    piperid-4-yl]urea (m.p. 254-255° C.)                         ______________________________________                                    

EXAMPLE 431-(4-Methoxybenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (prepared accordingto Example 1) is hydrolysed by refluxing in 2N sodium hydroxide to give[1-(naphth-2-ylmethyl)piperid-4-yl]urea (m.p. 183°-5° C.). The productis acylated by reaction with 4-methoxybenzoyl chloride to give the titlecompound, m.p. of HCl, quarterhydrate=193°-193.5° C.).

EXAMPLES 44-45

In a manner analogous to Example 1,2-bromomethylnaphthalene was reactedwith the following compounds of formula II:

4-benzylureidopiperidine,

4-(p-fluorobenzoyl)ureidopiperidine

to give the following compounds of formula I:

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        44.         1-Benzyl-3-[1-naphth-2-ylmethyl)-                                             piperid-4-yl]urea (m.p. of HCl,                                               1/4 hydrate salt = 243-247° C. (dec)).                     45.         1-(p-Fluorobenzoyl)-3-[1-(naphth-2-                                           ylmethyl)piperid-4-yl]urea (m.p. of                                           HCl, 1/4 hydrate salt = 242-245° C. (dec)).                ______________________________________                                    

EXAMPLES 46-54

Using a procedure analogous to Example 1,4-benzoylureidopiperidine isreacted with the following compounds:

2-(naphth-2-yl)ethyl tosylate,

6-cyanonaphth-2-ylmethyl bromide,

6-fluoronaphth-2-ylmethyl bromide,

6-bromonaphth-2-ylmethyl bromide,

1-(naphth-2-yl)propyl chloride,

di-(naphth-2-ylmethyl)sulphate,

6-chloromethylquinoxaline,

3-chloromethylcinnoline,

6-chloromethylisoquinoline,

to give the following compounds

    ______________________________________                                        Example No. Compound                                                          ______________________________________                                        46.         1-Benzoyl-3-[1-(2-[naphth-2-yl]ethyl)-                                        piperid-4-yl]urea, (m.p. of HCl salt =                                        230-232° C.).                                              47.         1-Benzoyl-3-[1-(6-cyanonaphth-2-yl-                                           methyl)piperid-4-yl]urea, (m.p. of HCl,                                       hemihydrate salt = 264-266° C.).                           48.         1-Benzoyl-3-[1-(6-fluoronaphth-2-yl-                                          methyl)piperid-4-yl]urea.                                         49.         1-Benzoyl-3-[1-(6-bromonaphth-2-yl-                                           methyl)piperid-4-yl]urea.                                         50.         1-Benzoyl-3-[1-[1-(naphth-2-yl)propyl]-                                       piperid-4-yl]urea.                                                51.         1-Benzoyl-3-[1-(naphth-2-ylmethyl)-                                           piperid-4-yl]urea, m.p. of HCl, hemi-                                         hydrate salt = 232°-234° C.).                       52.         1-Benzoyl-3-[1-(quinoxalin-6-ylmethyl)-                                       piperid-4-yl]urea.                                                53.         1-Benzoyl-3-[1-(cinnolin-3-ylmethyl)-                                         piperid-4-yl]urea.                                                54.         1-Benzoyl-3-[1-(isoquinolin-6-ylmethyl)-                                      piperid-4-yl]urea.                                                ______________________________________                                    

EXAMPLE 55 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

2-Bromomethylnaphthalene is heated with 4-benzoylureidopyridine inacetonitrile solvent to give1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium urea bromide m.p.247°-8° C. This compound is reduced by refluxing with sodium borohydridein isopropyl alcohol solvent to give the title compound, m.p. of HClhemihydrate salt=232°-234° C.

Alternatively 1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium]ureabromide is reduced with sodium borohydride in methanol solvent to give1-benzoyl-3-[1-(naphth-2-ylmethyl)-3,4-dehydropiperid-4-yl]urea. Thiscompound may then be reduced by refluxing with sodium borohydride inisopropyl alcohol to give the title compound.

EXAMPLE 56 1-Benzoyl-1-methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

1-Methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (1.4 g.) (prepared byreacting 4-amino-1-(naphth-2-ylmethyl)piperidine with methyl isocyanate)in toluene (30 cm³) was acylated using benzoyl chloride (0.92 g) inpresence of pyridine (0.6 g) to give the title compound: m.p. of HCl,hemihydrate salt=164°-166° C.

Analysis: Found: C 67.37; H, 6.58; N, 9.45; C₂₅ H₂₇ N₃ O₂.HCl1/2H₂ Orequires C 67.18; H, 6.54; N, 9.40%.

EXAMPLE 57 1-Benzoyl-3-methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

Using a procedure analogous to Example 37,4-methylamino-1-(naphth-2-ylmethyl)piperidine was reacted withbenzoylurea to give the title compound. m.p. of HCl,quarterhydrate=207°-209° C.

EXAMPLE 58N-[[[1-(2-Naphthalenylmethyl)-4-piperidinyl]amino]carbonyl]-2-furancarboxamide

4-Amino-1-(naphth-2-ylmethyl)piperidine (1.2 g, 0.005 m) and2-furoylurea (0.7 g) in pyridine (5 ml) was refluxed for 6 hours, thencooled. Water was added and the precipitate collected by filtration. Thesolid was dissolved in chloroform with a little methanol and filtered.The solvent was removed under reduced pressure and the residue waspurified by medium pressure liquid chromatography on silica using CHCl₃: MeOH (9:1 v/v) as eluent. The isolated product (1st component eluted)was dissolved in ethyl acetate and acidified with ethanolic HCl to givea precipitate. This was filtered and dried to give 0.3 g of the titlecompound as the HCl, 3/4 H₂ O salt, mp. 157°-159° C.

Analysis: Found: C61.95, H 6.02, N,9.00% C₂₂ H₂₃ N₃ O₃.HCl.3/4H₂ Orequires C,61.82, H, 6.01, N, 9.83.

EXAMPLE 59 1-(pyrid-3-oyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]-urea

A suspension of the 4-amino-1-(naphth-2-ylmethyl)piperidine,hydrochloride (1.65 g, 5.97 mmol) and nicotinoylurea (0.82 g, 5 mmol) inpyridine (12 cm³) was stirred and refluxed for 5 hours thentriethylamine was added dropwise until a solution was formed. Heatingwas continued for 1 hour then the solution was allowed to cool to roomtemperature overnight. On the next day the mixture was heated untilhomogeneous then diluted with water, cooled in ice and the precipitatesolid collected and sucked dry on the sinter.

The solid was suspended in boiling ethanol and ethanolic HCl was addedto give an acidic solution. On cooling a gum deposited which wasseparated by decantation and put to one side. The supernatant solutioncrystallised on further cooling and the deposited solid was collectedand recrystallised from ethanol containing a little methanol to give afirst crop of the title compound.

The gum obtained above was triturated with warm ethanol untilcrystalline then the solid was recrystallised from ethanol containing alittle methanol. The sample was dissolved in methanol, treated withdecolourising charcoal in the usual manner, then recovered byevaporation. The glassy residue was recrystallised from ethanol and theproduct combined with the first crop obtained above to give the titlecompound as the dihydrochloride salt, mp=205°-7° C.

Analysis: Found: C 60.23; H, 5.87; N, 12.09% C₂₃ H₂₄ N₄ O₂.2HCl requiresC 59.87; H, 5.68; N 12.14%.

EXAMPLE 60N-[[[1-(6-Quinolinylmethyl)-4-piperidinyl]amino]carbonyl]benzamide

A mixture of 6-bromomethylquinoline HBr (1.4 g, 4.59 mmol),4-benzoylureidopiperidine (1.14 g, 4.62 mmol), triethylamine (1.2 g,11.88 mmol) and dry DMF (15 ml) was prepared at 0° C. The mixture wasstirred for 0.5 hours at 0° C. then at room temperature overnight. More6-bromomethyquinoline (0.3 g, 0.98 mmol) was added and stirringcontinued for 5.5 hours. The mixture was diluted with water (20 ml) andcooled in ice to give a solid which was collected, washed with water anddried. The solid was suspended in boiling ethanol (15 ml) and ethanolicHCl added to give an acidic solution which rapidly crystallised. Thiswas cooled in ice, the solid collected, and dried to give the titlecompound as the dihydrochloride, ethanolate quarterhydrate salt (1.22g,) mp 242°-4° C., phase change ca 204° C.

Analysis: Found: C 58.60, H, 6.34, N 11.28% C₂₃ H₂₄ N₄O₂.2HCl.EtOH.1/4H₂ O requires C, 58.65; H,6.4; N, 10.94.

EXAMPLE 61 1-(pyrid-2-oyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea

Sodium (0.1 g, 4.35 mmol) in liquid ammonia (100-150 cm³) was stirreduntil the blue colour was discharged. A bomb was charged with[1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.83 g, 2.93 mmol) and theliquid ammonia solution was added. The mixture was stirred at roomtemperature for 2 days then the bomb was cooled to -78° C., and ethylpicolinate (0.6 g, 3.97 mmol) was added. Stirring was continued for 3hours at room temperature then the ammonia was allowed to evaporate andthe gummy residue triturated with water then ethyl acetate. The ethylacetate suspension was filtered to give recovered[1-(naphth-2-ylmethyl)piperid-4-yl]urea (0.33 g). The filtrate wasevaporated and the residue chromatographed on silica eluting withchloroform then chloroform: ethyl acetate 4:1 to give the title compound(0.37 g).

Analysis: Found: C 71.37; H, 6.33; N, 14.07% C₂₃ H₂₄ N₄ O₂ requires C.71.11, H, 6.23, N, 14.42%.

EXAMPLE 62N[[[1-[(6-Fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-3-pyridinecarboxamide

A solution of 2-bromomethyl-6-fluoronaphthalene (99 g) indimethylformamide (400 ml) was added over 1 hour to a stirred suspensionN-[[[4-piperidinyl]amino]carbonyl-3-pyridinecarboxamide (102.5 g) indimethylformamide (1000 ml) and diisopropylethylamine (72 ml). Afterstirring for a further hour the reaction was diluted with water and theprecipitated product collected, washed with water, then ether and driedto give 132 g (78.5%). The base was dissolved in chloroform (700 ml) andadded to a solution of maleate acid (40 g) in ethanol (400 ml) toprecipitate the maleate salt of the title compound 142 g (65.8%) m.p.206°-207° C.

Analysis

C₂₃ H₂₃ N₄ FO₂.C₄ H₄ O₄ requires: C, 62.1; H, 5.2; N, 10.7% Found: C,61.7; H,5.2; N, 10.6%

EXAMPLE 63N-[[[1-[(6-Fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino]carbonyl]-4-pyridinecarboxamide

A mixture of 4-amino-1-[(6-fluoro-2-naphthalenyl)methyl]piperidine (1.3g, 5 mmol), 4-pyridoylurea (0.9 g, 5 mmol) and pyridine (6 ml) wasstirred at reflux for 16 hours. The solution was diluted with water (8ml) and the precipitated dark brown product collected by filtration togive 1.5 g. The crude product was dissolved in chloroform (25 ml),shaken with decolourising charcoal, filtered and evaporated. The residuewas suspended in hot ethanol (20 ml) and succinic acid (0.44 g) added togive a clear solution which crystallised on standing. The productcrystals were collected by filtration and washed with ethanol to givethe succinate salt of the title compound. m.p. 187°-188° C.

Analysis C₂₃ H₂₃ N₄ FO₂.C₄ H₆ O₄ requires: C, 61.82; H, 5.57; N, 10.68%Found: C, 61.89; H, 5.66; N, 10.51%

EXAMPLE 64

The compound of example 62 when in the form of the free base has an m.p.199°-200° C. The citrate salt has an m.p. 141°-142° C. Themonohydrochloride 3/4 H₂ O salt has an m.p. 242°-244° C.

EXAMPLE 653-Methoxy-N-[[[1-(2-quinolinylmethyl)-4-piperidinyl]amino]carbonyl]benzamid

2-(2-Chloromethyl)quinoline hydrochloride (0.642 g, 3 mmol) was added toa stirred solution of3-methoxy-N-[[[4-piperidinyl]amino]carbonyl]benzamide (0.832 g, 3 mmol),and triethylamine (1.25 cm³, 9 mmol) in dimethylformamide (6 cm³)maintained at 70° C. Heating and stirring were maintained for a further1 hour. The mixture was then cooled and diluted with water toprecipitate a gum. The product solidified on standing/stirring and wascollected, washed with water, and crystallised twice from ethanol togive the title compound 0.8 g (63.7%). This was suspended in hot ethanoland acidified with ethanolic hydrogen chloride to precipitate thehydrochloride salt of the title compound. Partial loss of HCl occurredon drying at 100° C. under vacuum and the title compound was finallyobtained as a one and one half hydrochloride 0.75 g (52.8%) m.p.208°-11° C.

Analysis C₂₄ H₂₆ N₄ O₃. 11/2 HCl requires: C, 60.92; H, 5.86; N, 11.84;Cl, 11.24% Found: C, 60.68; H, 5.80; N, 11.97; Cl 10.35%

EXAMPLE 66N-[[[1-(6-Quinolinylmethyl)-4-piperidinyl]amino]carbonyl]3-pyridinecarboxamide

4-Amino-1-(quinol-6-ylmethyl)piperidine(1.3 g 5.4 mmol) andnicotinoylurea (0.6 g, 3.64 mmol) were refluxed vigorously in pyridine(2 ml) for 4.5 hours. The solution was cooled and diluted with ethylacetate, the precipitated solid was collected and washed well with ethylacetate to give 1.08 g of a solid. This was chromatographed on a shortsilica column eluting with chloroform methanol (9:1 v/v) to give 0.89 gof the title compound, mp 196°-8° C.

Analysis C₂₂ H₂₃ N₅ O₂ requires: C, 67.85; H, 5.95; N 17.98. Found: C,67.89; H, 5.86; N, 17.85%

We claim:
 1. A compound of the formula: ##STR22## wherein n is 0 or 1;R¹, R², R³ and R⁴ are independently hydrogen or C₁ -C₄ alkyl;X is ═O or═S; Y is --O-- or a direct bond; Z is --CO-- or --CH₂ --; R is 2, 3 or4-pyridyl or 2, 3 or 4-pyridyl substituted by one or two substituentsselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, fluoro, chloro,bromo, chloroethyl, trifluoromethyl, and nitro, and; Ar is 2, 4, 5 or6-quinolinyl or 2,4,5 or 6-quinolinyl substituted by one or twosubstituents selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, fluoro,chloro, bromo, chloroethyl, trifluoromethyl, amino, C₁ -C₄ alkylamino,di-(C₁ -C₄ alkyl)amino, C₁ -C₄ alkylcarbonylamino, dimethane ordiethanesulphonylamino, nitro or cyano, ora pharmaceutically acceptableacid addition or quaternary ammonium salt thereof, in which the dottedline represents an optional double bond.
 2. A compound of claim 1 inwhich Y is a direct bond.
 3. A compound of claim 1 in which Z is --CO--.4. A compound of claim 1 in which Ar is 2- or 6-quinolinyl.
 5. Acompound of claim 1 in which R is 2, 3 or 4-pyridyl.
 6. A compound ofclaim 1 in which R is 3-pyridyl.
 7. A compound of claim 1 which isN-[[[1-(6-quinolinylmethyl)-4-piperidinyl]amino]carbonyl]-3-pyridinecarboxamide,or a pharmaceutically acceptable acid addition or quaternary ammoniumsalt thereof.
 8. A pharmaceutical composition comprising an amounteffective to alleviate depression of a compound of claim 1 or apharmaceutically acceptable acid addition or quaternary ammonium saltthereof and a pharmaceutically acceptable carrier.
 9. A compound of theformula: ##STR23## wherein R¹, R², R³ and R⁴ are independently hydrogenor C₁ -C₄ alkyl;X is ═O or ═S; Y is --O-- or a direct bond; Z is --CO--or --CH₂ --; R is 2, 3 or 4-pyridyl or 2, 3 or 4-pyridyl substituted byone or two substituents selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy,hydroxy, fluoro, chloro, bromo, chloroethyl, trifluoromethyl, and nitro,and; Ar is 3, 4, 5 or 6-isoquinolinyl or 3,4,5 or 6-isoquinolinylsubstituted by one or two substituents selected from C₁ -C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro, chloro, bromo, chloroethyl,trifluoromethyl, amino, C₁ -C₄ alkylamino, di-(C₁ -C₄ alkyl)amino, C₁-C₄ alkylcarbonylamino, dimethane or diethanesulphonylamino, nitro orcyano, ora pharmaceutically acceptable acid addition or quaternaryammonium salt thereof, in which the dotted line represents an optionaldouble bond.
 10. A compound of claim 1 in which Y is a direct bond. 11.A compound of claim 1 in which Z is --CO--.
 12. A compound of claim 1 inwhich Ar is 3- or 6-isoquinolinyl.
 13. A compound of claim 1 in which Ris 2, 3 or 4-pyridyl.
 14. A compound of claim 1 in which R is 3-pyridyl.15. A pharmaceutical composition comprising an amount effective toalleviate depression of a compound of claim 9 or a pharmaceuticallyacceptable acid addition or quaternary ammonium salt thereof and apharmaceutically acceptable carrier.
 16. A method for alleviatingdepression in a mammal afflicted with depression, which comprisesadministering to said mammal an amount effective to alleviate depressionof a compound of the formula ##STR24## wherein R is 3 or 4-pyridyl;andAr is unsubstituted-6-quinolinyl, unsubstituted-6-isoquinolinyl, or2-quinolinyl or 3-isoquinolinyl which may be substituted at the 6 and/or7 position by one or two substituents selected from methyl, ethyl,propyl, isopropyl, fluoro or chloro, ora pharmaceutically acceptableacid addition or quaternary ammonium salt thereof, in which the dottedline represents an option double bond.
 17. A method of claim 16 in whichR is 3-pyridyl.
 18. A method of claim 16 in which Ar is 6-quinolinyl or6-isoquinoliny.
 19. A method of claim 16 in which Ar is 2-quinolinyl or3-isoquinolinyl unsubstituted or substituted at the 6 and/or 7 positionwith fluoro.
 20. A method of claim 16 in which the given compound of theformula isN-[[[1-(6-quinolinylmethyl)-4-piperidinyl]amino]carbonyl]-3-pyridinecarboxamideor a pharmaceutically acceptable acid addition or quaternary ammoniumsalt thereof.